Substance abuse is a serious threat to society for which effective therapies are sought. Since no single effective treatment for substance abuse has been identified, current strategies seek to combine behavioral and pharmacological therapies. Successful pharmaceutical therapies include the agonist-based maintenance therapies: methadone (for heroin abuse) and nicotine patches (for tobacco abuse). Despite a profound understanding of the pharmacological actions of these drugs, the basis for their therapeutic effects remain unclear. In addition, no effective treatment has been found for cocaine abuse. Behavioral data from animal models may improve methods for developing these medications. Drugs that can decrease drug self-administration without having effects on other behaviors may be potential candidates. We recently developed a promising series of findings on the treatment of cocaine-maintained responding with the selective dopamine (DA) reuptake inhibitor GBR 12909. Acute administration abolished cocaine-maintained responding, while having no effect on food-maintained responding. Repeated administration sustained this effect, and a single injection of a long-acting decanoate formulation decreased cocaine-maintained responding for almost thirty days, while having little or no effect on food-maintained responding. While the behavioral effects of GBR 12909 and its decanoate appear very promising, their physiological effects may warrant further study. For example, cocaine has cardiovascular effects, and the potential of these drugs for interaction with this effect should be explored. Lastly, the effects of agonist-based treatments are likely to depend upon both specific pharmacological actions and behavioral factors. Our collaborators continue to modify the GBR series to improve its pharmacology and we also propose testing additional drugs as potential adjuvants to improve the effects of GBR analogs. The specific aims of this grant are to 1) further evaluate the effects of an ultra long-acting formulation of GBR 12909 alone and in combination with other drugs, 2) assess the behavioral effects of novel GBR 12909 analogs, with the aim of identifying improved decanoate candidates, and 3) assess the effects of GBR 12909 analogs and GBR 12909 decanoate alone, and in combination with cocaine, on cardiovascular functioning. These studies are designed to extend the agonist-based approach to the development of potential medications for the treatment of cocaine abuse and further our understanding of the behavioral pharmacology of the self-administration of cocaine.